After starring roles in European films, including an acclaimed performance in the Taviani Brothers' Fiorile, and several smaller film roles, Vartan had noticeable supporting roles in major Hollywood movies, including Never Been Kissed (1999), One Hour Photo (2002) and Monster-in-Law (2005). In 2007, he appeared in the Australian horror film Rogue, and starred in the film Jolene in 2008.
Vartan's most notable role to date has been as Michael Vaughn in the American television series Alias (2001–2006). He played the role of Lancelot in TNT's production of Marion Zimmer Bradley's The Mists of Avalon (2001). Vartan has also had guest appearances on Friends (as Dr. Tim Burke, Tom Selleck's character's son) and Ally McBeal (as Jonathan Basset). He also appeared on the show Kitchen Confidential, which starred his former Alias co-star Bradley Cooper, as a French chef who was Cooper's rival. In September 2007, Vartan played James Walker, a main role in the ABC drama Big Shots. However, the show was canceled after one season.